Suizhou Central Hospital

OBJECTIVE: To assess the efficacy and safety of hydroxychloroquine plus standard of care compared with standard of care alone in adults with coronavirus disease 2019 (covid-19). DESIGN: Multicentre, open label, randomised controlled trial. SETTING: 16 government designated covid-19 treatment centres in China, 11 to 29 February 2020. PARTICIPANTS: 150 patients admitted to hospital with laboratory confirmed covid-19 were included in the intention to treat analysis (75 patients assigned to hydroxychloroquine plus standard of care, 75 to standard of care alone). INTERVENTIONS: Hydroxychloroquine administrated at a loading dose of 1200 mg daily for three days followed by a maintenance dose of 800 mg daily (total treatment duration: two or three weeks for patients with mild to moderate or severe disease, respectively). MAIN OUTCOME MEASURE: Negative conversion of severe acute respiratory syndrome coronavirus 2 by 28 days, analysed according to the intention to treat principle. Adverse events were analysed in the safety population in which hydroxychloroquine recipients were participants who received at least one dose of hydroxychloroquine and hydroxychloroquine non-recipients were those managed with standard of care alone. RESULTS: Of 150 patients, 148 had mild to moderate disease and two had severe disease. The mean duration from symptom onset to randomisation was 16.6 (SD 10.5; range 3-41) days. A total of 109 (73%) patients (56 standard of care; 53 standard of care plus hydroxychloroquine) had negative conversion well before 28 days, and the remaining 41 (27%) patients (19 standard of care; 22 standard of care plus hydroxychloroquine) were censored as they did not reach negative conversion of virus. The probability of negative conversion by 28 days in the standard of care plus hydroxychloroquine group was 85.4% (95% confidence interval 73.8% to 93.8%), similar to that in the standard of care group (81.3%, 71.2% to 89.6%). The difference between groups was 4.1% (95% confidence interval -10.3% to 18.5%). In the safety population, adverse events were recorded in 7/80 (9%) hydroxychloroquine non-recipients and in 21/70 (30%) hydroxychloroquine recipients. The most common adverse event in the hydroxychloroquine recipients was diarrhoea, reported in 7/70 (10%) patients. Two hydroxychloroquine recipients reported serious adverse events. CONCLUSIONS: Administration of hydroxychloroquine did not result in a significantly higher probability of negative conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients. TRIAL REGISTRATION: ChiCTR2000029868.

Abstract Objective To evaluate sintilimab versus placebo in combination with chemotherapy (cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil) as first line treatment of unresectable locally advanced, recurrent, or metastatic oesophageal squamous cell carcinoma. Design Multicentre, randomised, double blind, phase 3 trial. Setting 66 sites in China and 13 sites outside of China between 14 December 2018 and 9 April 2021. Participants 659 adults (aged ≥18 years) with advanced or metastatic oesophageal squamous cell carcinoma who had not received systemic treatment. Intervention Participants were randomised 1:1 to receive sintilimab or placebo (3 mg/kg in patients weighing <60 kg or 200 mg in patients weighing ≥60 kg) in combination with cisplatin 75 mg/m 2 plus paclitaxel 175 mg/m 2 every three weeks. The trial was amended to allow investigators to choose the chemotherapy regimen: cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil (800 mg/m 2 continuous infusion on days 1-5). Main outcome measures Overall survival in all patients and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1. Results 659 patients were randomly assigned to sintilimab (n=327) or placebo (n=332) with chemotherapy. 616 of 659 patients (93%) received sintilimab or placebo in combination with cisplatin plus paclitaxel and 43 of 659 patients (7%) received sintilimab or placebo in combination with cisplatin plus 5-fluorouracil. At the interim analysis, sintilimab with chemotherapy showed better overall survival compared with placebo and chemotherapy in all patients (median 16.7 v 12.5 months, hazard ratio 0.63, 95% confidence interval 0.51 to 0.78, P<0.001) and in patients with combined positive scores of ≥10 (17.2 v 13.6 months, 0.64, 0.48 to 0.85, P=0.002). Sintilimab and chemotherapy significantly improved progression free survival compared with placebo and chemotherapy in all patients (7.2 v 5.7 months, 0.56, 0.46 to 0.68, P<0.001) and in patients with combined positive scores of ≥10 (8.3 v 6.4 months, 0.58, 0.45 to 0.75, P<0.001). Adverse events related to treatment occurred in 321 of 327 patients (98%) in the sintilimab-chemotherapy group versus 326 of 332 (98%) patients in the placebo-chemotherapy group. Rates of adverse events related to treatment, grade ≥3, were 60% (196/327) and 55% (181/332) in the sintilimab-chemotherapy and placebo-chemotherapy groups, respectively. Conclusions Compared with placebo, sintilimab in combination with cisplatin plus paclitaxel showed significant benefits in overall survival and progression free survival as first line treatment in patients with advanced or metastatic oesophageal squamous cell carcinoma. Similar benefits of sintilimab with cisplatin plus 5-fluorouracil seem promising. Trial registration ClinicalTrials.gov NCT03748134 .

BACKGROUND: Early control of elevated blood pressure is the most promising treatment for acute intracerebral haemorrhage. We aimed to establish whether implementing a goal-directed care bundle incorporating protocols for early intensive blood pressure lowering and management algorithms for hyperglycaemia, pyrexia, and abnormal anticoagulation, implemented in a hospital setting, could improve outcomes for patients with acute spontaneous intracerebral haemorrhage. METHODS: We performed a pragmatic, international, multicentre, blinded endpoint, stepped wedge cluster randomised controlled trial at hospitals in nine low-income and middle-income countries (Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, and Viet Nam) and one high-income country (Chile). Hospitals were eligible if they had no or inconsistent relevant, disease-specific protocols, and were willing to implement the care bundle to consecutive patients (aged ≥18 years) with imaging-confirmed spontaneous intracerebral haemorrhage presenting within 6 h of the onset of symptoms, had a local champion, and could provide the required study data. Hospitals were centrally randomly allocated using permuted blocks to three sequences of implementation, stratified by country and the projected number of patients to be recruited over the 12 months of the study period. These sequences had four periods that dictated the order in which the hospitals were to switch from the control usual care procedure to the intervention implementation of the care bundle procedure to different clusters of patients in a stepped manner. To avoid contamination, details of the intervention, sequence, and allocation periods were concealed from sites until they had completed the usual care control periods. The care bundle protocol included the early intensive lowering of systolic blood pressure (target <140 mm Hg), strict glucose control (target 6·1-7·8 mmol/L in those without diabetes and 7·8-10·0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature ≤37·5°C), and rapid reversal of warfarin-related anticoagulation (target international normalised ratio <1·5) within 1 h of treatment, in patients where these variables were abnormal. Analyses were performed according to a modified intention-to-treat population with available outcome data (ie, excluding sites that withdrew during the study). The primary outcome was functional recovery, measured with the modified Rankin scale (mRS; range 0 [no symptoms] to 6 [death]) at 6 months by masked research staff, analysed using proportional ordinal logistic regression to assess the distribution in scores on the mRS, with adjustments for cluster (hospital site), group assignment of cluster per period, and time (6-month periods from Dec 12, 2017). This trial is registered at Clinicaltrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787) and is completed. FINDINGS: Between May 27, 2017, and July 8, 2021, 206 hospitals were assessed for eligibility, of which 144 hospitals in ten countries agreed to join and were randomly assigned in the trial, but 22 hospitals withdrew before starting to enrol patients and another hospital was withdrawn and their data on enrolled patients was deleted because regulatory approval was not obtained. Between Dec 12, 2017, and Dec 31, 2021, 10 857 patients were screened but 3821 were excluded. Overall, the modified intention-to-treat population included 7036 patients enrolled at 121 hospitals, with 3221 assigned to the care bundle group and 3815 to the usual care group, with primary outcome data available in 2892 patients in the care bundle group and 3363 patients in the usual care group. The likelihood of a poor functional outcome was lower in the care bundle group (common odds ratio 0·86; 95% CI 0·76-0·97; p=0·015). The favourable shift in mRS scores in the care bundle group was generally consistent across a range of sensitivity analyses that included additional adjustments for country and patient variables (0·84; 0·73-0·97; p=0·017), and with different approaches to the use of multiple imputations for missing data. Patients in the care bundle group had fewer serious adverse events than those in the usual care group (16·0% vs 20·1%; p=0·0098). INTERPRETATION: Implementation of a care bundle protocol for intensive blood pressure lowering and other management algorithms for physiological control within several hours of the onset of symptoms resulted in improved functional outcome for patients with acute intracerebral haemorrhage. Hospitals should incorporate this approach into clinical practice as part of active management for this serious condition. FUNDING: Joint Global Health Trials scheme from the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, and the Medical Research Council and Wellcome Trust; West China Hospital; the National Health and Medical Research Council of Australia; Sichuan Credit Pharmaceutic and Takeda China.

BACKGROUND: Intrauterine adhesion (IUA) is one of the most serious complications in patients with endometrial repair disorder after injury. Currently, there is no effective treatment for IUA. Stem cell is the main candidate of new therapy, which functions mainly through paracrine mechanism. Stem-derived exosomes (Exo) play an important role in tissue injury. Here, we mainly aim to study the effect of bone marrow mesenchymal stem cell (BMSC)-derived Exo on repairing endometrium of IUA animal models and its effect on TGF-β1 induced EMT in endometrial epithelial cells (EECs). METHODS: Totally, 64 female rabbits were randomly divided into Sham operation group, model group, BMSC treatment group, and Exo treatment group. EMT in EECs was induced by TGF-β1. Then, EECs were treated with Exo (25 μg/ml, 50 μg/ml, 100 μg/ml) for 24 h. HE staining and Masson staining were used to evaluate the changes in glandular number and fibrosis area. The expression levels of CK19 and VIM were detected by immunohistochemistry. Western blotting was used to detect the expression of CK19, VIM, FSP-1, E-cadherin, TGF-β1, TGF-β1R, Smad 2, and P-Smad 2. RT-PCR was used to detect mRNA expression levels of CK19, VIM, FSP-1, E-cadherin, TGF-β1, TGF-β1R, and Smad 2. RESULTS: Compared with the model group, the number of endometrial glands was significantly increased and endometrial fibrosis area was significantly decreased in BMSC and Exo groups (P < 0.05). CK19 level significantly increased whereas VIM level significantly decreased after treatment of BMSCs and Exo (P < 0.05). Additionally, the expressions of TGF-β1, TGF-β1R, and Smad2 mRNA were all significantly decreased after BMSC and Exo treatment (P < 0.05). Besides, phosphorylation levels of TGF-β1, TGF-β1R, and Smad2 were also significantly decreased in BMSC and Exo treatment groups (P < 0.05). Furthermore, there was no significant difference between BMSC and Exo treatment groups (P > 0.05). EMT was induced in EECs by 60 ng/ml TGF-β1 for 24 h. After Exo treatment for 24 h, mRNA expressions of CK-19 and E-cadherin increased, while those of VIM, FSP-1, TGF-β1, and Smad2 decreased. Additionally, protein expressions of CK-19 and E-cadherin increased, while those of VIM, FSP-1, TGF-β1, Smad2, and P-Smad2 decreased. CONCLUSIONS: BMSC-derived Exo is involved in the repair of injured endometrium, with similar effect to that of BMSC, and can reverse EMT in rabbit EECs induced by TGF-β1. BMSC-derived Exo may promote endometrial repair by the TGF-β1/Smad signaling pathway.

Non-small cell lung cancer is one of the most common types of malignances worldwide and the main cause of cancer-related deaths. Current treatment for NSCLC is based on surgical resection, chemotherapy, radiotherapy, and targeted therapy, with poor therapeutic effectiveness. In recent years, immune checkpoint inhibitors have applied in NSCLC treatment. A large number of experimental studies have shown that immune checkpoint inhibitors are safer and more effective than traditional therapeutic modalities and have allowed for the development of better guidance in the clinical treatment of advanced NSCLC patients. In this review, we describe clinical trials using ICI immunotherapies for NSCLC treatment, the available data on clinical efficacy, and the emerging evidence regarding biomarkers.

Abstract Objectives To assess the efficacy and safety of hydroxychloroquine (HCQ) plus standard–of–care (SOC) compared with SOC alone in adult patients with COVID–19. Design Multicenter, open–label, randomized controlled trial. Setting 16 government–designated COVID–19 treatment centers in China through 11 to 29 in February 2020. Participants 150 patients hospitalized with laboratory confirmed COVID–19 were included in the intention to treat analysis. 75 patients were assigned to HCQ plus SOC and 75 to SOC alone. Interventions HCQ was administrated with a loading dose of 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days (total treatment duration: 2 or 3 weeks for mild/moderate or severe patients, respectively). Main outcome measures The primary outcome was whether participants had a negative conversion of SARS–CoV–2 by 28 days, and was analyzed according to the intention–to–treat principle. Adverse events were analyzed in the safety population in which HCQ recipients were participants who actually received at least one dose of HCQ and HCQ non–recipients were those actually managed with SOC alone. Results Among 150 patients, 148 were with mild to moderate disease and 2 were with severe disease. The mean days (± standard deviation, min to max) from symptoms onset to randomization was 16.6 (±10.5 days, 3 to 41 days). The negative conversion probability by 28 days in SOC plus HCQ group was 85.4% (95% confidence interval (CI) 73.8% to 93.8%), similar to that in the SOC group 81.3% (95%CI 71.2% to 89.6%). Between–group difference was 4.1% (95%CI –10.3% to 18.5%). In the safety population, adverse events were recorded in 7 (8.8%) HCQ non–recipients (N=80) and in 21 (30%) HCQ recipients (N=70). The most common adverse event in the HCQ recipients was diarrhea, reported in 7 (10%) patients. Two HCQ recipients reported serious adverse events. Conclusions The administration of HCQ did not result in a significantly higher negative conversion probability than SOC alone in patients mainly hospitalized with persistent mild to moderate COVID–19. Adverse events were higher in HCQ recipients than in HCQ non–recipients. Trial registration ChiCTR2000029868 What is already known on this topic — The pandemic of coronavirus disease 2019 (COVID–19) imposes substantial burdens on individuals, communities, health–care facilities, markets, governments, etc. globally. — There is no specific treatment approved for COVID–19 or vaccine to prevent infection with the novel coronavirus. — During the urgent pandemic, media headlines the utility of drugs without solid evidence but buries the side–effects of these drugs. What this study adds — In this randomized clinical trial of patients mainly with persistent mild to moderate COVID–19, exposure to hydroxychloroquine led to a similar probability of virus elimination comparing to the current standard–of–care. — Adverse events, mostly gastrointestinal related, were significantly increased in patients who received hydroxychloroquine. — Overall, the results from our trial do not support the use of hydroxychloroquine in patients with persistent mild to moderate COVID–19. Print abstract Study question To assess the efficacy and safety of hydroxychloroquine (HCQ) plus standard–of–care (SOC) compared with SOC alone in adult patients with COVID–19. Methods This is a multicenter, open–label, randomized controlled trial conducted in 16 government–designated COVID–19 treatment centers in China through 11 to 29 in February 2020. A total of 150 patients hospitalized with laboratory confirmed COVID–19 were included in the intention to treat analysis. Among them, 75 patients were assigned to HCQ plus SOC and 75 to SOC alone. HCQ was administrated with a loading dose of 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days (total treatment duration: 2 or 3 weeks for mild/moderate or severe patients, respectively). The primary outcome was whether participants had a negative conversion of SARS–CoV–2 by 28 days, and was analyzed according to the intention to treat principle. Adverse events were analyzed in the safety population in which HCQ recipients were participants who actually received at least one dose of HCQ and HCQ non–recipients were those actually managed with SOC alone. Study answer and limitations Among 150 patients, 148 were with mild to moderate disease and 2 were with severe disease. The mean days (± standard deviation, min to max) from symptoms onset to randomization was 16.6 (±10.5 days, 3 to 41 days). The negative conversion probability by 28 days in SOC plus HCQ group was 85.4% (95% confidence interval (CI) 73.8% to 93.8%), similar to that in the SOC group 81.3% (95%CI 71.2% to 89.6%). Between–group difference was 4.1% (95%CI –10.3% to 18.5%). In the safety population, adverse events were recorded in 7 (8.8%) HCQ non–recipients (N=80) and in 21 (30%) HCQ recipients (N=70) with two serious adverse events. The most common adverse event in the HCQ recipients was diarrhea, reported in 7 (10%) patients. Two HCQ recipients reported serious adverse events. What this study adds Our trial does not support the use of hydroxychloroquine in patients with persistent mild to moderate COVID–19 due to limited effects on virus eliminating and significantly increased adverse events. Funding, competing interests, data sharing This work was supported by the Emergent Projects of National Science and Technology (2020YFC0844500), National Natural Science Foundation of China (81970020, 81770025), National Key Research and Development Program of China (2016YFC0901104), Shanghai Municipal Key Clinical Specialty (shslczdzk02202, shslczdzk01103), National Innovative Research Team of High–level Local Universities in Shanghai, Shanghai Key Discipline for Respiratory Diseases (2017ZZ02014), National Major Scientific and Technological Special Project for Significant New Drugs Development (2017ZX09304007), Key Projects in the National Science and Technology Pillar Program during the Thirteenth Five–year Plan Period (2018ZX09206005–004, 2017ZX10202202–005–004, 2017ZX10203201–008). All authors declared no competing interests. Anonymized datasets can be made available on reasonable request after approval from the trial management committee. Study registration ChiCTR2000029868

Importance: Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown. Objective: To investigate whether dual antiplatelet therapy (DAPT) is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded end point, noninferiority randomized clinical trial included 760 patients with acute minor nondisabling stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5, with ≤1 point on the NIHSS in several key single-item scores; scale range, 0-42). The trial was conducted at 38 hospitals in China from October 2018 through April 2022. The final follow-up was on July 18, 2022. Interventions: Eligible patients were randomized within 4.5 hours of symptom onset to the DAPT group (n = 393), who received 300 mg of clopidogrel on the first day followed by 75 mg daily for 12 (±2) days, 100 mg of aspirin on the first day followed by 100 mg daily for 12 (±2) days, and guideline-based antiplatelet treatment until 90 days, or the alteplase group (n = 367), who received intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg) followed by guideline-based antiplatelet treatment beginning 24 hours after receipt of alteplase. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 (range, 0-6), at 90 days. The noninferiority of DAPT to alteplase was defined on the basis of a lower boundary of the 1-sided 97.5% CI of the risk difference greater than or equal to -4.5% (noninferiority margin) based on a full analysis set, which included all randomized participants with at least 1 efficacy evaluation, regardless of treatment group. The 90-day end points were assessed in a blinded manner. A safety end point was symptomatic intracerebral hemorrhage up to 90 days. Results: Among 760 eligible randomized patients (median [IQR] age, 64 [57-71] years; 223 [31.0%] women; median [IQR] NIHSS score, 2 [1-3]), 719 (94.6%) completed the trial. At 90 days, 93.8% of patients (346/369) in the DAPT group and 91.4% (320/350) in the alteplase group had an excellent functional outcome (risk difference, 2.3% [95% CI, -1.5% to 6.2%]; crude relative risk, 1.38 [95% CI, 0.81-2.32]). The unadjusted lower limit of the 1-sided 97.5% CI was -1.5%, which is larger than the -4.5% noninferiority margin (P for noninferiority <.001). Symptomatic intracerebral hemorrhage at 90 days occurred in 1 of 371 participants (0.3%) in the DAPT group and 3 of 351 (0.9%) in the alteplase group. Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke presenting within 4.5 hours of symptom onset, DAPT was noninferior to intravenous alteplase with regard to excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03661411.

Abstract Cutaneous wound healing, especially diabetic wound healing, is a common clinical challenge. Reactive oxygen species (ROS) and bacterial infection are two major detrimental states that induce oxidative stress and inflammatory responses and impede angiogenesis and wound healing. A derivative of the metabolite itaconate, 4‐octyl itaconate (4OI) has attracted increasing research interest in recent years due to its antioxidant and anti‐inflammatory properties. In this study, 4OI‐modified black phosphorus (BP) nanosheets are incorporated into a photosensitive, multifunctional gelatin methacrylamide hydrogel to produce a new photothermal therapy (PTT) and photodynamic therapy (PDT) system with antibacterial and antioxidant properties for diabetic wound regeneration. Under laser irradiation, the 4OI–BP‐entrapped hydrogel enables rapid gelation, forming a membrane on wounds, and offers high PTT and PDT efficacy to eliminate bacterial infection. Without laser irradiation, BP acts as a carrier and controls the release of 4OI, with which it synergistically enhances antioxidant activity, thus alleviating excessive ROS damage to endothelial cells, promoting neovascularization, and facilitating faster diabetic wound closure. These findings indicate that 4OI–BP‐entrapped multifunctional hydrogel provides a stepwise countermeasure with antibacterial and antioxidant properties for enhanced diabetic wound healing and may lead to novel therapeutic interventions for diabetic ulcers.

OBJECTIVES: Long non-coding RNAs (lncRNAs) have been demonstrated as crucial regulators in cancer, but whether they are involved in the immune response of cancer cells remains largely undiscovered. GATA3-AS1 is a novel lncRNA that was upregulated in breast cancer (BC) according to online databases. However, its role in triple-negative breast cancer (TNBC) was elusive. METHODS: GATA3-AS1 expression in BC tissues and adjacent normal tissues was obtained from online databases. Loss-of-function assays were designed and conducted to verify the functional role of GATA3-AS1 in TNBC cells. Bioinformatic analysis and mechanism experiments were applied to explore the downstream molecular mechanism of GATA3-AS1. Similarly, the upstream mechanism which led to the upregulation of GATA3-AS1 in TNBC cells was also investigated. RESULTS: GATA3-AS1 was markedly overexpressed in TNBC tissues and cells. Knockdown of GATA3-AS1 suppressed TNBC cell growth and enhanced the resistance of TNBC cells to immune response. GATA3-AS1 induced the deubiquitination of PD-L1 through miR-676-3p/COPS5 axis. GATA3-AS1 destabilized GATA3 protein by promoting GATA3 ubiquitination. CONCLUSION: GATA3-AS1 contributed to TNBC progression and immune evasion through stabilizing PD-L1 protein and degrading GATA3 protein, offering a new target for the treatment of TNBC.

Abstract Repairing infected bone defects is a challenge in the field of orthopedics because of the limited self‐healing capacity of bone tissue and the susceptibility of refractory materials to bacterial activity. Innervation is the initiating factor for bone regeneration and plays a key regulatory role in subsequent vascularization, ossification, and mineralization processes. Infection leads to necrosis of local nerve fibers, impeding the repair of infected bone defects. Herein, a biomaterial that can induce skeletal‐associated neural network reconstruction and bone regeneration with high antibacterial activity is proposed for the treatment of infected bone defects. A photosensitive conductive hydrogel is prepared by incorporating magnesium‐modified black phosphorus (BP@Mg) into gelatin methacrylate (GelMA). The near‐infrared irradiation‐based photothermal and photodynamic treatment of black phosphorus endows it with strong antibacterial activity, improving the inflammatory microenvironment and reducing bacteria‐induced bone tissue damage. The conductive nanosheets and bioactive ions released from BP@Mg synergistically improve the migration and secretion of Schwann cells, promote neurite outgrowth, and facilitate innerved bone regeneration. In an infected skull defect model, the GelMA‐BP@Mg hydrogel shows efficient antibacterial activity and promotes bone and CGRP + nerve fiber regeneration. The phototherapy conductive hydrogel provides a novel strategy based on skeletal‐associated innervation for infected bone defect repair.

BACKGROUND: Neuroinflammation is one of the most important processes in secondary injury after traumatic brain injury (TBI). Triggering receptor expressed on myeloid cells 2 (TREM2) has been proven to exert neuroprotective effects in neurodegenerative diseases and stroke by modulating neuroinflammation, and promoting phagocytosis and cell survival. However, the role of TREM2 in TBI has not yet been elucidated. In this study, we are the first to use COG1410, an agonist of TREM2, to assess the effects of TREM2 activation in a murine TBI model. METHODS: Adult male wild-type (WT) C57BL/6 mice and adult male TREM2 KO mice were subjected to different treatments. TBI was established by the controlled cortical impact (CCI) method. COG1410 was delivered 1 h after CCI via tail vein injection. Western blot analysis, immunofluorescence, laser speckle contrast imaging (LSCI), neurological behaviour tests, brain electrophysiological monitoring, Evans blue assays, magnetic resonance imaging (MRI), and brain water content measurement were performed in this study. RESULTS: The expression of endogenous TREM2 peaked at 3 d after CCI, and it was mainly expressed on microglia and neurons. We found that COG1410 improved neurological functions within 3 d, as well as neurological functions and brain electrophysiological activity at 2 weeks after CCI. COG1410 exerted neuroprotective effects by inhibiting neutrophil infiltration and microglial activation, and suppressing neuroinflammation after CCI. In addition, COG1410 treatment alleviated blood brain barrier (BBB) disruption and brain oedema; furthermore, COG1410 promoted cerebral blood flow (CBF) recovery at traumatic injury sites after CCI. In addition, COG1410 suppressed neural apoptosis at 3 d after CCI. TREM2 activation upregulated p-Akt, p-CREB, BDNF, and Bcl-2 and suppressed TNF-α, IL-1β, Bax, and cleaved caspase-3 at 3 d after CCI. Moreover, TREM2 knockout abolished the effects of COG1410 on vascular phenotypes and microglial states. Finally, the neuroprotective effects of COG1410 were suppressed by TREM2 depletion. CONCLUSIONS: Altogether, we are the first to demonstrate that TREM2 activation by COG1410 alleviated neural damage through activation of Akt/CREB/BDNF signalling axis in microglia after CCI. Finally, COG1410 treatment improved neurological behaviour and brain electrophysiological activity after CCI.

The average age of hyperuricemia patients has gradually decreased, but young patients with primary hyperuricemia often do not exhibit clinical symptoms and have not received sufficient attention. However, a lack of symptoms with primary hyperuricemia does not mean that high serum uric acid (UA) levels cannot lead to pathological effects, such as oxidative stress and inflammation, and the specific damage is still unclear. We aimed to determine the relationship between oxidative stress and inflammation to explore the possible role of pathological damage in asymptomatic young patients with primary hyperuricemia.A total of 333 participants were enrolled in our study: 158 asymptomatic young patients with primary hyperuricemia and 175 healthy persons from a health check-up population. Malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and general biochemical markers were measured.We found no differences in biochemical markers (fasting glucose, TG, TC, LDL-C, HDL-C, SCr, BUN, AST, and ALT) between the patients and healthy persons. Subsequent analyses of oxidative stress and inflammation revealed that the serum levels of MDA, IL-6, and TNF-α in the patients were significantly higher than those in the healthy control group (P < .001), and the SOD activity was significantly lower (P < .001). As the UA levels increased, MDA increased significantly and SOD decreased significantly; likewise, IL-6 and TNF-α increased significantly as the UA level increased. MDA showed a significant positive correlation with IL-6 (r = 0.367, P < .001) and TNF-α (r = 0.319, P < .001), and SOD was negatively correlated with IL-6 (r = -0.241, P < .01) and TNF-α (r = -0.308, P < .001). Multivariable logistic regression analysis showed that UA (OR: 2.379, 95% CI: 1.698-3.286, P < .001; OR: 3.261, 95% CI: 1.729-3.857, P < .001; for IL-6 and TNF-α, respectively) and MDA (OR: 1.836, 95% CI: 1.283-2.517, P < .01; OR: 2.532, 95% CI: 1.693-3.102, P < .001; for IL-6 and TNF-α, respectively) were risk factors for high IL-6 and TNF-α and that SOD (OR: 0.517, 95% CI: 0.428-0.763, P < .01; OR: 0.603, 95% CI: 0.415-0.699, P < .001; for IL-6 and TNF-α, respectively) was a protective factor.In our study, some abnormal pathological effects were found in asymptomatic young patients with hyperuricemia, suggesting that in young hyperuricemia patients, oxidative stress, inflammation and the inflammatory response may be related to the oxidative stress induced by UA. Therefore, we should pay more attention to the pathological damage caused by these alterations.

In this study we provide the first report of the characteristics, comorbidities,<br/>laboratory and x-ray findings, and clinical outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients with pre-existing liver cirrhosis. The cause of death in most patients was respiratory failure rather than progression of liver disease. Lower numbers of blood lymphocytes and platelets, and higher bilirubin levels might represent indicators of poor outcome in this patient population.<br/><br/><br/><br/><br/><br/>

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, coronavirus disease 2019 (COVID-19), affecting more than seventeen million people around the world. Diagnosis and treatment guidelines for clinicians caring for patients are needed. In the early stage, we have issued "A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)"; now there are many direct evidences emerged and may change some of previous recommendations and it is ripe for develop an evidence-based guideline. We formed a working group of clinical experts and methodologists. The steering group members proposed 29 questions that are relevant to the management of COVID-19 covering the following areas: chemoprophylaxis, diagnosis, treatments, and discharge management. We searched the literature for direct evidence on the management of COVID-19, and assessed its certainty generated recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Recommendations were either strong or weak, or in the form of ungraded consensus-based statement. Finally, we issued 34 statements. Among them, 6 were strong recommendations for, 14 were weak recommendations for, 3 were weak recommendations against and 11 were ungraded consensus-based statement. They covered topics of chemoprophylaxis (including agents and Traditional Chinese Medicine (TCM) agents), diagnosis (including clinical manifestations, reverse transcription-polymerase chain reaction (RT-PCR), respiratory tract specimens, IgM and IgG antibody tests, chest computed tomography, chest x-ray, and CT features of asymptomatic infections), treatments (including lopinavir-ritonavir, umifenovir, favipiravir, interferon, remdesivir, combination of antiviral drugs, hydroxychloroquine/chloroquine, interleukin-6 inhibitors, interleukin-1 inhibitors, glucocorticoid, qingfei paidu decoction, lianhua qingwen granules/capsules, convalescent plasma, lung transplantation, invasive or noninvasive ventilation, and extracorporeal membrane oxygenation (ECMO)), and discharge management (including discharge criteria and management plan in patients whose RT-PCR retesting shows SARS-CoV-2 positive after discharge). We also created two figures of these recommendations for the implementation purpose. We hope these recommendations can help support healthcare workers caring for COVID-19 patients.

BACKGROUND: Sepsis is one of the most common diseases that seriously threaten human health. Although a large number of markers related to sepsis have been reported in the last two decades, the diagnostic accuracy of these biomarkers remains unclear due to the lack of similar baselines among studies. Therefore, we conducted a large systematic review and meta-analysis to evaluate the diagnostic value of biomarkers from studies that included non-infectious systemic inflammatory response syndrome patients as a control group. METHODS: We searched Medline, Embase and the reference lists of identified studies beginning in April 2014. The last retrieval was updated in September 2016. RESULTS: Ultimately, 86 articles fulfilled the inclusion criteria. Sixty biomarkers and 10,438 subjects entered the final analysis. The areas under the receiver operating characteristic curves for the 7 most common biomarkers, including procalcitonin, C-reactive protein, interleukin 6, soluble triggering receptor expressed on myeloid cells-1, presepsin, lipopolysaccharide binding protein and CD64, were 0.85, 0.77, 0.79, 0.85, 0.88, 0.71 and 0.96, respectively. The remaining 53 biomarkers exhibited obvious variances in diagnostic value and methodological quality. CONCLUSIONS: Although some biomarkers displayed moderate or above moderate diagnostic value for sepsis, the limitations of the methodological quality and sample size may weaken these findings. Currently, we still lack an ideal biomarker to aid in the diagnosis of sepsis. In the future, biomarkers with better diagnostic value as well as a combined diagnosis using multiple biomarkers are expected to solve the challenge of the diagnosis of sepsis.

BACKGROUND: The application of microRNAs (miRNAs) as potential biomarkers and therapy targets has been widely investigated in many kinds of cancers. The discovery of tumor associated miRNAs in serum of patients supported the use of plasma/serum miRNAs as noninvasive means of cancer detection. However, the aberrant expression of miRNAs in bladder cancer patients and their intensive roles and mechanisms in bladder cancer are poorly understood. METHODS: Taqman probe stem-loop real-time PCR was used to accurately measure the levels of miR-19a in bladder cancer cell lines, 100 pairs of bladder cancer tissues and the adjacent non-neoplastic tissues and also the plasma collected from bladder cancer patients and normal controls. miR-19a mimics and inhibitors were transfected into bladder cancer cells to investigate its role on regulating cell proliferation which was measured by CCK-8 and colony formation assay. The target of miR-19a was identified by western blot and whether its regulatory role depends on its target was improved by a rescue experiment with miR-19a mimic and PTEN expression plasmid. RESULTS: miR-19a was significantly up-regulated in bladder cancer tissues and high-level of miR-19a was correlative with more aggressive phenotypes of bladder cancer. Meanwhile, gain or loss of function of miR-19a demonstrated that miR-19a can promote cell growth of bladder cancer cells and the further mechanism studies indicated that its oncogenic role was dependent on targeting PTEN. Furthermore, investigation of miR-19a expression in the plasma of bladder cancer patients showed that miR-19a was also increased in plasma of bladder cancer patients which strongly supported miR-19a could be developed as potential diagnostic marker of bladder cancer. CONCLUSIONS: Our data indicated that miR-19a might act as an oncogenic microRNA in bladder cancer and was significantly up-regulated in bladder cancer carcinogenesis. The oncogenic role of miR19a in bladder cancer was dependent on targeting PTEN.

The outbreak of coronavirus disease 2019 (COVID-19) is having a dramatic effect on the mental health of healthcare workers (HCWs). Upon the emergence of the COVID-19 pandemic, the Chinese government dispatched about 42 000 HCWs to Wuhan City and Hubei Province to fight this pandemic. This study briefly examines front-line nurses who experienced burnout, with the main objective of investigating the mediating roles of positive and negative affect in the relationship between resilience and burnout in Wuhan hospitals at the peak of the COVID-19 pandemic. A total of 180 front-line nurses voluntarily participated via a social media group. They completed the online questionnaires, including the Maslach Burnout Inventory-General Survey (MBI-GS), the Positive and Negative Affect Schedule (PANAS), the Connor-Davidson Resilience Scale (CD-RISC), demographics, and work-related characteristics. Structural equation modelling (SEM) analysis was used to examine the mediating effect of positive and negative affect on the relationship between resilience and burnout. The total prevalence of burnout was 51.7%, of which 15.0% were severe burnout. These preliminary results revealed that positive and negative affect fully mediated the effects of resilience on burnout, emotional exhaustion, depersonalization, and reduced personal accomplishment of front-line nurses. It is necessary to know the impact of resilience on HCWs with burnout through the positive and negative affect of individual backgrounds and situations, and how policymakers can deploy resilience interventions to support front-line HCWs.

Intracranial aneurysm subarachnoid hemorrhage (SAH) is a cerebrovascular disorder associated with high overall mortality. Currently, the underlying mechanisms of pathological reaction after aneurysm rupture are still unclear, especially in the immune microenvironment, inflammation, and relevant signaling pathways. SAH-induced immune cell population alteration, immune inflammatory signaling pathway activation, and active substance generation are associated with pro-inflammatory cytokines, immunosuppression, and brain injury. Crosstalk between immune disorders and hyperactivation of inflammatory signals aggravated the devastating consequences of brain injury and cerebral vasospasm and increased the risk of infection. In this review, we discussed the role of inflammation and immune cell responses in the occurrence and development of aneurysm SAH, as well as the most relevant immune inflammatory signaling pathways [PI3K/Akt, extracellular signal-regulated kinase (ERK), hypoxia-inducible factor-1α (HIF-1α), STAT, SIRT, mammalian target of rapamycin (mTOR), NLRP3, TLR4/nuclear factor-κB (NF-κB), and Keap1/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/ARE cascades] and biomarkers in aneurysm SAH. In addition, we also summarized potential therapeutic drugs targeting the aneurysm SAH immune inflammatory responses, such as nimodipine, dexmedetomidine (DEX), fingolimod, and genomic variation-related aneurysm prophylactic agent sunitinib. The intervention of immune inflammatory responses and immune microenvironment significantly reduces the secondary brain injury, thereby improving the prognosis of patients admitted to SAH. Future studies should focus on exploring potential immune inflammatory mechanisms and developing additional therapeutic strategies for precise aneurysm SAH immune inflammatory regulation and genomic variants associated with aneurysm formation.

BACKGROUND AND PURPOSE: ANRIL has long been considered as the strongest candidate gene at the 9p21 locus, robustly associated with stroke and coronary artery disease. However, the underlying molecular mechanism remains unknown. The present study works to elucidate such a mechanism. METHODS: Using expression quantitative loci analysis, we identified potential genes whose expression may be influenced by genetic variation in ANRIL. To verify the identified gene(s), knockdown and overexpression of ANRIL were evaluated in human umbilical vein endothelial cells and HepG2 cells. Ischemic stroke and coronary artery disease risk were then evaluated in the gene(s) demonstrated to be mediated by ANRIL in 3 populations of Chinese Han ancestry: 2 ischemic stroke populations consisting of the Central China cohort (903 cases and 873 controls) and the Northern China cohort (816 cases and 879 controls) and 1 coronary artery disease cohort consisting of 772 patients and 873 controls. RESULTS: Expression quantitative loci analysis identified CARD8 among others, with knockdown of ANRIL expression decreasing CARD8 expression and overexpression of ANRIL increasing CARD8 expression. The minor T allele of a previously identified CARD8 variant (rs2043211) was found to be significantly associated with a protective effect of ischemic stroke under the recessive model in 2 independent stroke cohorts. No significant association was found between rs2043211 and coronary artery disease. CONCLUSIONS: CARD8 is a downstream target gene regulated by ANRIL. Single nucleotide polymorphism rs2043211 in CARD8 is significantly associated with ischemic stroke. ANRIL may increase the risk of ischemic stroke through regulation of the CARD8 pathway.

Non-alcoholic fatty liver disease (NAFLD) is considered to be a manifestation of liver metabolic damage and is related to insulin resistance and genetic susceptibility. Inflammation mediated by Kupffer cells (KCs) is of critical importance to the development of NAFLD. The primary role of KCs in NAFLD is considered to be the perturbation of the C-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) pathways as a result of lipopolysaccharide (LPS) recognition by Toll-like receptor 4 (TLR4). Simultaneously, the activation of NF-κB, as mediated by oxidative and endoplasmic reticulum (ER) stress and free fatty acid (FFA) or free cholesterol (FC) crystal formation, heavily relies on NF-κB regulatory factors and TLR4. Additionally, the imbalance of certain pro-inflammatory cytokines and chemokines released by innate immunity is deemed to promote the steatosis of hepatocytes. In conclusion, this review indicates that the inflammatory and oxidative stress of KCs play a significant role in the development of NAFLD.